Skeletal muscle tissue is repaired and maintained for the lifetime of mammalian organisms with the exception of functional muscle loss and atrophy in the aged. The adult stem cell thought to be responsible for re- generating and maintaining skeletal muscle tissue is the satellite cell, so named for its anatomical localization in skeletal muscle tissue sandwiched between the plasma membrane of the myofiber and the extracellular matrix. This unique niche imposes asymmetry on the satellite cell, allowing signaling from the external environment as well as from the underlying myofiber. The mechanisms involved in the renewal of the satellite cell are not well understood as a number of groups have identified subsets of satellite cells that exhibit enhanced engraftment into skeletal muscle tissue. A number of groups, including ours have shown that engrafted satellite cells are capable of self-renewal during skeletal muscle repair. A number of important questions regarding satellite cell self-renewal have not been addressed. When do satellite cells self-renew? How are satellite cell numbers maintained? What mechanisms are responsible for satellite cell self-renewal? Are all satellite cells equivalent? These basic questions regarding satellite cell self-renewal remain unanswered. Additional analysis has revealed that satellite-SP cells express JamB, a junctional adhesion protein involved in cell polarity, which binds the Par complex is present in satellite-SP cells. Second, Jam-B cells express Par-3, which is asymmetric and co-localizes with asymmetric Syndecan-4. When prospectively isolated, Syndecan-4+/Jam-B+ cultures maintain Pax7 expressing "reserve" cells while Pax7 is not detectable in Syndecan-4+Jam-B- satellite cell ex- plants, which all terminally differentiate. Our recently submitted manuscript provides evidence for a signaling pathway whereby asymmetric localization of Par complex in turn asymmetrically activates p38????MAPK inducing MyoD in one daughter cell during the first satellite cell division following explant. The other daughter fails to induce MyoD and re-acquires a quiescent "reserve" phenotype. We propose that Syndecan-4 and Jam- B signaling coordinated by extracellular signals commits a satellite cell to asymmetric division. A primary goal of our experimental plan is to test this hypothesis and provide evidence for a Syndecan-47Jam-B complex that is required for asymmetric division of satellite cells. PUBLIC HEALTH RELEVANCE: Skeletal muscle is essential for respiration, locomotion, and elimination of waste. Severe loss of skeletal muscle is catastrophic, shortening lifespan, dramatically reducing overall quality of life and incurring significant health care costs. Severe loss of muscle function occurs during normal aging and in neuromuscular diseases. The loss of skeletal muscle function is likely due to loss of regenerative capacity and the ability of adult muscle stem cells to renew themselves. We propose research to better understand how adult muscle stem cells are regulated aiding in the development of stem cell therapies.